Dissociation between Ionic Remodeling and Ability to Sustain Atrial Fibrillation during Recovery from Experimental Congestive Heart Failure

Abstract

Background-Congestive heart failure (CHF) downregulates atrial transient outward (Ito), slow delayed rectifier (IKs), and L-type Ca2+ (ICa,L) currents and upregulates Na +-Ca2+ exchange current (INCX) (ionic remodeling) and causes atrial fibrosis (structural remodeling). The relative importance of ionic versus structural remodeling in CHF-related atrial fibrillation (AF) is controversial. Methods and Results-We measured hemodynamic and echocardiographic parameters, mean duration of burst pacing-induced AF (DAF), and atrial-myocyte ionic currents in dogs with CHF induced by 2-week ventricular tachypacing (240 bpm), CHF dogs allowed to recover without pacing for 4 weeks (REC), and unpaced controls. Left ventricular ejection fraction averaged 58.6±1.2% (control), 36.2±2.3% (CHF, P<0.01), and 57.9±1.6% (REC), indicating full hemodynamic recovery. Similarly, left atrial pressures were 2.2±0.3 (control), 13.1±1.5 (CHF), and 2.4±0.4 (REC) mm Hg. CHF reduced Ito density by ≈65% (P<0.01), decreased ICa,L density by ≈50% (P<0.01), and diminished IKs density by ≈40% (P<0.01) while increasing I NCX density by ≈110% (P<0.05). In REC, all ionic current densities returned to control values. DAF increased in CHF (1132±207 versus 14.3±8.8 seconds, control) and remained increased with REC (1014±252 seconds). Atrial fibrous tissue content also increased in CHF (2.1±0.2% for control versus 10.2±0.7% for CHF, P<0.01), with no recovery observed in REC (9.4±0.8%, P<0.01 versus control, P=NS versus CHF). Conclusions-With reversal of CHF, there is complete recovery of ionic remodeling, but the prolonged-AF substrate and structural remodeling remain. This suggests that structural, not ionic, remodeling is the primary contributor to AF maintenance in experimental CHF.